Breakthrough Clinical Results
Klotho Neurosciences announced it is progressing with manufacturing and process development for KLTO-202, a gene therapy targeting amyotrophic lateral sclerosis (ALS). KLTO-202 utilizes a neuroprotective RNA splice variant of the alpha-Klotho gene (s-KL), shown to have favorable therapeutic outcomes in animal models. The company anticipates completing manufacturing and process development in eight months, followed by FDA meetings, animal safety studies, IND filing, and site preparation. Phase I/II clinical trials in ALS patients are projected to begin in the third quarter of the following year. The company will leverage contract research organizations (CROs) to manage manufacturing and clinical trials.
Key Highlights
- Klotho Neurosciences is advancing manufacturing of KLTO-202, a gene therapy for ALS.
- KLTO-202 leverages a neuroprotective RNA splice variant of the alpha-Klotho gene (s-KL).
- Preclinical studies in animal models showed favorable therapeutic outcomes.
- Phase I/II clinical trials are expected to start in Q3 of the following year.
Incidence and Prevalence
Global ALS Incidence and Prevalence Estimates
Incidence Rates by Region
The annual incidence rate of ALS varies significantly across different regions globally:
- In Japan, a nationwide survey conducted in 2013 found an annual incidence rate of 2.2 per 100,000 people (95% CI 2.1-2.3)
- When adjusted for age and sex using the 2000 U.S. standard population, Japan's rate was 2.3 per 100,000 people (95% CI 2.2-2.4)
- Cuba reported an adjusted death rate from ALS for the population older than 15 years of 0.83 per 100,000
- Brazil showed adjusted mortality rates of 0.61 to 0.89 per 100,000 person-years over 20 years, and 1.77 to 2.3 per 100,000 person-years over 45 years
- In London, the adjusted incidence in people of African ancestry was 1.35 per 100,000 person-years (95% CI 0.72-2.3) compared to 1.97 per 100,000 person-years (95% CI 1.55-2.48) in those of European ancestry
- Middleborough, Massachusetts showed a notably higher ALS incidence of 2.51 deaths per 100,000 person-years compared to the statewide rate of 1.26 per 100,000 person-years (1969-1985)
Prevalence
- In Japan, the annual crude prevalence rate was 9.9 per 100,000 people (95% CI 9.7-10.1)
Ethnic Variations
Ethnic variations in ALS incidence have been consistently observed:
- Brazil showed a predominance of ALS in Caucasians with an odds ratio of 2.92 (95% CI 2.78-3.07)
- The odds ratio in blacks was significantly lower at 0.04 (95% CI: 0.03-0.04)
- Similarly low odds ratios were found in mestizos (0.05; 0.04-0.07) and Indians (0.02; 0.01-0.04)
- In Cuba, the adjusted mortality rate per 100,000 was considerably lower in the mixed population (0.55; CI 0.4-0.72) than in whites (0.93; CI 0.83-1.03) and blacks (0.87; CI 0.62-1.17)
- The overall mortality rate from ALS in Cuba is similar to that described in Hispanic populations in the United States and is lower than in Northern European populations
Age and Gender Patterns
- In Japan, the age group with the highest prevalence and incidence was 70-79 years, with a male-female ratio of approximately 1.5
- Brazil reported an average age of ALS patients of 62.7 ± 13.2 years, with a predominance of males (1.3:1)
- In Cuba, the mean age at death was 63.7 years with a slight male predominance (1.1:1)
Genetic Factors
- Approximately 10% of ALS cases have a family history
- Pathogenic variants in the SOD1 gene are the second most frequent causative factor of genetics-based ALS worldwide, after C9ORF72 hexanucleotide repeat expansion
- Research has identified clinically significant pathogenetic variants in 14.43% of ALS cases
Key Unmet Needs and Target Populations for ALS
Unmet Medical Needs
Pre-symptomatic detection and intervention represents a critical unmet need in ALS care. Research indicates that understanding the pre-symptomatic phase could "transform our understanding of key events in pathogenesis" and "dramatically accelerate progress towards disease prevention." Related to this is the need for improved biomarkers that are "critically important to studying pre-symptomatic ALS and essential to efforts to intervene therapeutically before clinically manifest disease emerges."
Despite significant research advances, the exact cause of ALS remains largely unknown. Translational challenges persist with "challenges to be overcome in order to achieve improved success rates for translating drugs from animal models to clinics for treating ALS." This highlights the need for novel preclinical protocol standards, potentially combining "animal models with human induced pluripotent stem cells (iPSCs)" to improve translational success.
Many healthcare systems, including Germany, may not be able to meet the complex needs of patients with ALS (pwALS) because non-medical services such as psychological support or social counselling are not regularly included in their care. Specialised neuropalliative care is not routinely implemented nor widely available. There is also a need for standardized quality of life measures, as "there is limited consensus regarding which are most valid, reliable, responsive, and interpretable."
Challenges remain in delivering RNA-based therapeutics to the central nervous system, and there is a clear need for assistive devices designed for ALS patients with limited upper extremity strength who are not confined to a wheelchair.
Target Populations
Research suggests distinct treatment approaches may be needed for different ALS subtypes: - Spinal-onset ALS (sALS) patients show gut-dysbiosis associated with disease severity - Bulbar-onset ALS (bALS) patients display oral-dysbiosis linked to symptom severity
These findings "support distinct microbial mechanisms underlying two ALS subtypes, which have been previously grouped together as a single disease."
Genetic factors affecting survival remain understudied, with research noting "a lack of a comprehensive study to elucidate the role of genetic factors in the survival of ALS." Recent studies have identified specific genes associated with shorter survival, including ATXN2 (HR: 3.6), C9orf72 (HR: 1.6), and FUS (HR: 1.8), highlighting the need for genotype-specific approaches.
At-risk carriers of ALS-associated genetic variants need "paradigms for providing appropriate clinical care" including genetic testing protocols, monitoring for early signs, and lifestyle recommendations. Increased access to predictive genetic counseling in a timely manner is a significant need given potential access to gene-specific therapies in the presymptomatic stage.
DNA methylation regulation represents an emerging target, with research showing "rare variants in the TET2 gene" significantly increase ALS risk (OR = 1.95).
Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them.
Current clinical trials, such as the TUDCA-ALS study, are targeting general ALS populations with add-on therapies to riluzole, while regulatory agencies are evaluating gene-specific therapies like Qalsody (Tofersen) for SOD1-associated ALS, highlighting the potential of gene-targeted therapies for specific genetic subgroups.
Drug used in other indications
KLTO-202 Clinical Trials Information
Based on the available information, there is no data regarding a drug or compound called "KLTO-202" being trialed for ALS or any other indications. The information about this compound, its clinical trials, intervention models, dosing regimens, or administration protocols is not present in the provided context.